Coumarin derivatives as ion channel openers

ABSTRACT

The present invention is directed to coumarin derivatives, pharmaceutical compositions containing them and their use in the treatment of disorders related to ion channels such as potassium channels.

CROSS REFERENCE TO RELATED APPLICATIONS

This Application is a divisional application of U.S. application Ser.No. 11/334,679, filed Jan. 18, 2006 now U.S. Pat. No. 7,662,975, whichclaims priority to U.S. Provisional Patent Application No. 60/645,702,filed Jan. 21, 2005, the disclosures of which are hereby incorporated byreference in their entireties.

FIELD OF THE INVENTION

The present invention is directed to novel coumarin derivatives,pharmaceutical compositions containing them and their use in thetreatment of disorders related to ion channels such as potassiumchannels. The compounds of the invention are thus useful for thetreatment of various disorders. This includes but is not limited tourinary incontinence, overactive bladder, hypertension, erectiledysfunction, female sexual disorders, dysmenorrhea, irritable bowlsyndrome, airway hyperactivity, epilepsy, stroke, Alzheimer's andParkinson's diseases, myocardial injury, coronary artery disease as wellas hair loss and baldness.

BACKGROUND OF THE INVENTION

Ion channels play a fundamental role in the homeostasis of cell functionthrough the regulation of the transmembrane movement of ions. Cellularactivity can be affected by modifications of the activities of the ionchannels. This leads to changes in membrane potential difference.Potassium channels are a diverse and ubiquitous group of ion channels.They principally regulate the resting membrane potential of the cell andattenuate the level of excitation of cells. A functional K_(ATP) channelis a hetero-octamer assembled from four inward rectifying potassiumchannel subunits (Kir6.2) and four sulfonylurea receptor (SUR) subunits.There are two SUR genes, SUR1 and SUR2. SUR1/Kir6.2 channels are foundin the pancreas and brain. Two major splice variants arise from the SUR2gene, SUR2A and SUR2B, that differ only at the C-terminal 42 aminoacids. SUR2A/Kir6.2 channels are found in cardiac and skeletal tissueswhereas SUR2B/Kir6.2 channels are found in smooth muscles of manytissues including bladder (Aguilar-Bryan, 1998). A number of diseases orconditions may be treated with potassium channel openers. This includesoveractive bladder, urinary incontinence, male erectile dysfunction,female sexual disorders, premature labor, benign prostate hyperplasia(BPH), dysmenorrhea, neurodegeneration, stroke, pain, coronary arterydisease, angina, ischemia, eating disorders, irritable bowl syndrome andalopecia.

Urinary incontinence (UI) is a disease that can affect the overallquality of life of a patient. Overactive bladder (OAB) is the mostprevalent form of UI, with reported prevalence rate from 40 to 70% ofall diagnosed UI cases (Wein, 2000). OAB is characterized by thesymptoms of increased urinary frequency, urgency, and involuntary lossof urine. A primary cause of OAB is an oversensitive bladder thatcontracts unexpectedly and involuntarily. The ideal pharmaceutical agentshould suppress the involuntary contraction while leaving the normalvoiding contractions intact. ATP-sensitive potassium channel openers(KCO) could serve as such agents. The ATP-sensitive potassium channels(K_(ATP)) are expressed in bladder smooth muscle and function as keyregulators of the resting membrane potential in these cells. Compoundsthat selectively open these channels hyperpolarize the cell and decreasecellular excitability, resulting in suppression of involuntary bladdercontractions, while leaving the normal micturition circuitry intact.

SUMMARY OF THE INVENTION

The present invention is directed to a compound of formula (I)

wherein

R¹ is selected from the group consisting of hydrogen, halogen, cyano,nitro, CF₃ and —O—SO₂—CF₃;

R² is selected from the group consisting of hydrogen, halogen, cyano,nitro, CF₃ and —O—SO₂—CF₃;

provided that R¹ and R² are not each hydrogen;

a is an integer from 0 to 1;

L¹ is selected from the group consisting of —C(O)—, —CH(OH)— and—C(O)—NR^(A)—; wherein R^(A) is selected from hydrogen or C₁₋₄alkyl;

R³ is selected from the group consisting of hydrogen, C₁₋₄alkyl,C₂alkenyl, aryl and heteroaryl; wherein the aryl or heteroaryl isoptionally substituted with one or more substituents independentlyselected from halogen, hydroxy, C₁₋₄alkyl, C₁₋₄alkoxy, cyano, nitro orCF₃;

alternatively, -L¹-R³ is selected from -MOM or -SEM;

provided that when a is 0 (L¹ is absent), then R³ is other than hydrogenor C₁₋₄alkyl;

provided further that when a is 1 and L¹ is —CH(OH)—, then R³ is otherthan hydrogen;

R⁴ is selected from the group consisting of hydrogen, aryl, —C(O)-aryl,6-membered heteroaryl and —C(O)-(6 membered heteroaryl); wherein thearyl or heteroaryl group, whether alone or as part of a substituentgroup is optionally substituted with one or more substituentsindependently selected from halogen, hydroxy, C₁₋₄alkyl, C₁₋₄alkoxy,cyano, nitro or CF₃;

provided that when R¹ is hydrogen or halogen, R² is hydrogen, a is 0 (L¹is absent) and R³ is 4-hydroxy-phenyl, then R⁴ is other than4-chlorophenyl;

provided further that when R¹ is halogen, R² is hydrogen, a is 1, L¹ is—C(O)NH— and R³ is phenyl, then R⁴ is other than hydrogen;

or a pharmaceutically acceptable salt thereof.

The present invention is further directed to3-(4-chloro-benzoyl)-4-methyl-2-oxo-2H-chromene-7-carbonitrile andpharmaceutically acceptable salts thereof.

Illustrative of the invention is a pharmaceutical composition comprisinga pharmaceutically acceptable carrier and any of the compounds describedabove. An illustration of the invention is a pharmaceutical compositionmade by mixing any of the compounds described above and apharmaceutically acceptable carrier. Illustrating the invention is aprocess for making a pharmaceutical composition comprising mixing any ofthe compounds described above and a pharmaceutically acceptable carrier.

Exemplifying the invention are methods of treating disorders related toion channels, preferably potassium ion channels, more preferablyATP-sensitive potassium ion channels, in a subject in need thereofcomprising administering to the subject a therapeutically effectiveamount of any of the compounds or pharmaceutical compositions describedabove.

An example of the invention is a method for treating a disorder selectedfrom the group consisting of urinary incontinence, overactive bladder,hypertension, erectile dysfunction, female sexual disorders,dysmenorrheal, irritable bowl syndrome, airway hyperactivity, epilepsy,stroke, Alzheimer's and Parkinson's diseases, myocardial injury,coronary artery disease, hair loss and baldness, in a subject in needthereof comprising administering to the subject an effective amount ofany of the compounds or pharmaceutical compositions described above.

Another example of the invention is the use of any of the compoundsdescribed herein in the preparation of a medicament for treating: (a)urinary incontinence, (b) overactive bladder, (c) hypertension, (d)erectile dysfunction, (e) female sexual disorders, (f) dysmenorrhea, (g)irritable bowl syndrome, (h) airway hyperactivity, (i) epilepsy, (j)stroke, (k) Alzheimer's disease, (l) Parkinson's disease, (m) myocardialinjury, (n) coronary artery disease, (o) hair loss or (p) baldness, in asubject in need thereof.

DETAILED DESCRIPTION OF THE INVENTION

The present invention is directed to compounds of formula (I)

wherein R¹, R², R³, R⁴, a and L¹ are as herein defined. The compounds ofthe present invention are to ion channels openers, more specifically,potassium channels openers. The compounds of the present are thus usefulfor treatment of various disorders including, but not limited to,urinary incontinence, overactive bladder, hypertension, erectiledysfunction, female sexual disorders, dysmenorrheal, irritable bowlsyndrome, airway hyperactivity, epilepsy, stroke, Alzheimer's andParkinson's diseases, myocardial injury, coronary artery disease, hairloss and baldness. Preferably, the compounds of the present inventionare useful in the treatment of urinary incontinence or overactivebladder.

In an embodiment of the present invention, R¹ is selected from the groupconsisting of hydrogen, halogen, cyano, CF₃ and —SO₂—CF₃. In anotherembodiment of the present invention, R¹ is selected from the groupconsisting of halogen, cyano and —SO₂—CF₃. Preferably, R¹ is selectedfrom the group consisting of fluoro, cyano and —SO₂—CF₃.

In an embodiment of the present invention, R² is selected from the groupconsisting of hydrogen, halogen, cyano, CF₃ and —SO₂—CF₃. In anotherembodiment of the present invention, R² is selected from the groupconsisting of hydrogen, cyano and —SO₂—CF₃. Preferably, R² is selectedfrom the group consisting of hydrogen, cyano and —SO₂—CF₃.

In an embodiment of the present invention, a is 0. In another embodimentof the present invention, a is 1.

In an embodiment of the present invention, L¹ is selected from the groupconsisting of —C(O)—, —CH(OH)— and —C(O)—NR^(A)—; wherein R^(A) isselected from hydrogen or C₁₋₄alkyl. In another embodiment of thepresent invention, L¹ is selected from the group consisting of —C(O)—,—CH(OH)— and C(O)—NR^(A)—; wherein R^(A) is selected from hydrogen,methyl or ethyl. Preferably, L¹ is selected from the group consisting of—C(O)—, —CH(OH)— and —C(O)—NH—.

In an embodiment of the present invention, R³ is selected from the groupconsisting of hydrogen, C₁₋₄alkyl and aryl; wherein the aryl isoptionally substituted with one or more independently selected fromhalogen, hydroxy, C₁₋₄alkyl, C₁₋₄alkoxy, cyano, nitro or CF₃. In anotherembodiment of the present invention, R³ is selected from the groupconsisting of hydrogen, C₁₋₄alkyl, —CH═CH—, and aryl; wherein the arylis optionally substituted with one or more independently selected fromhalogen. Preferably, R³ is selected from the group consisting ofhydrogen, methyl, —CH═CH—, 2-chlorophenyl, 3-chlorophenyl,4-chlorophenyl, 2,3-dichlorophenyl, 2,4,-dichlrophenyl,2,4,6-trichlorophenyl, 2-fluorophenyl and 2,4-difluorophenyl.

In an embodiment of the present invention, R³ is other than hydrogen. Inanother embodiment of the present invention, R³ is heteroaryl; whereinthe heteroaryl is optionally substituted with one or more independentlyselected from halogen, hydroxy, C₁₋₄alkyl, C₁₋₄alkoxy, cyano, nitro orCF₃.

In an embodiment of the present invention, L¹-R³ is MOM or SEM.Preferably, L¹-R³ is MOM.

In an embodiment of the present invention, R⁴ is selected from the groupconsisting of hydrogen, —CH═CH—, aryl and —C(O)-aryl; wherein the aryl,whether alone or as part of a substituent group, is optionallysubstituted with one or more independently selected from halogen,hydroxy, C₁₋₄alkyl, C₁₋₄alkoxy, cyano, nitro or CF₃. In anotherembodiment of the present invention, R⁴ is selected from the groupconsisting of hydrogen, aryl and —C(O)-aryl; wherein the aryl isoptionally substituted with one to two substituents independentlyselected from hydroxy, halogen, C₁₋₄alkoxy or cyano. Preferably, R⁴ isselected from the group consisting of hydrogen, 2,4-dihydroxyphenyl,2,4-dimethoxyphenyl, 2-hydroxy-4-cyano-phenyl and4-chlorophenyl-carbonyl.

In another embodiment of the present invention, R⁴ is selected from thegroup consisting of 6-membered heteroaryl and —C(O)-(6 memberedheteroaryl); wherein the 6-membered heteroaryl, whether alone or as partof a substituent group, is optionally substituted with one or moreindependently selected from halogen, hydroxy, C₁₋₄alkyl, C₁₋₄alkoxy,cyano, nitro or CF₃.

In another embodiment of the present invention, is a compound selectedfrom the group consisting of3-(4-chloro-benzoyl)-4-methyl-2-oxo-2H-chromene-7-carbonitrile andpharmaceutically acceptable salts thereof.

In an embodiment of the present invention is any single compound orsubset of compounds selected from the representative compounds listed inTables 1 below.

Additional embodiments of the present invention, include those whereinthe substituents selected for one or more of the variables definedherein (i.e. R¹, R², R³, R⁴, a and L¹) are independently selected to beany individual substituent or any subset of substituents selected fromthe complete list as defined herein.

Representative compounds of the present invention are as listed inTables 1 below.

TABLE 1

ID No. R¹ R² (L¹)_(a) R³ R⁴ 2 —O—SO₂—CF₃ H —CH₂—O— methyl 2,4-dimethoxy-phenyl 3 cyano H absent (a = 0) methyl 4-chloro-phenyl- carbonyl- 4cyano H —C(O)— 4-chloro-phenyl H 6 cyano H —CH₂—O— methyl 2,4-dimethoxy-phenyl 7 —O—SO₂—CF₃ H —CH₂—O— H 2,4-dihydroxy- phenyl 8 cyano H —CH₂—O—H 2,4-dihydroxy- phenyl 9 cyano H absent (a = 0) allyl 2,4-dihydroxy-phenyl 11 fluoro H absent (a = 0) allyl 2-hydroxy-4- cyano-phenyl 12—O—SO₂—CF₃ H —CH(OH)— 2,4-dichloro- H phenyl 13 —O—SO₂—CF₃ H —C(O)—NH—2,4,6-trichloro- H phenyl 14 cyano H —CH(OH)— 2,4-dichloro- H phenyl 15cyano H —C(O)—NH— 2,4-difluoro- H phenyl 16 cyano H —C(O)—NH—2-fluoro-phenyl H 17 cyano H —C(O)—NH— 2-chloro-phenyl H 18 cyano H—C(O)—NH— 3-chloro-phenyl H 19 cyano H —C(O)—NH— 2,3-dichloro- H phenyl20 H cyano —CH(OH)— 2,4-dichloro- H phenyl 21 H cyano —C(O)—3-chloro-phenyl H 22 H —O—SO₂—CF₃ —C(O)— 3-chloro-phenyl H

As used herein, “halogen” shall mean chlorine, bromine, fluorine andiodine.

As used herein, the term “alkyl” whether used alone or as part of asubstituent group, include straight and branched chains. For example,alkyl radicals include methyl, ethyl, n-propyl, isopropyl, n-butyl,isobutyl, sec-butyl, t-butyl, pentyl and the like. Similarly, the term“C₁₋₄alkyl” whether used alone or as part of a substituent group,include straight and branched chains containing 4 carbon atoms. Forexample, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl,sec-butyl and t-butyl.

As used herein, unless otherwise noted, “alkoxy” whether used alone oras part of a substituent group, shall denote an oxygen ether radical ofthe above described straight or branched chain alkyl groups. Forexample, methoxy, ethoxy, n-propoxy, sec-butoxy, t-butoxy, n-hexyloxyand the like. Similarly, the term “C₁₋₄alkoxy” whether used alone or aspart of a substituent group, shall denote an oxygen ether radical of theabove described straight or branched chain C₁₋₄alkyl groups. Forexample, methoxy, ethoxy, n-propoxy, sec-butoxy, t-butoxy, and the like.

As used herein, unless otherwise noted, “aryl” shall refer tounsubstituted carbocylic aromatic groups such as phenyl, naphthyl, andthe like.

As used herein, unless otherwise noted, “heteroaryl” shall denote anyfive or six membered monocyclic aromatic ring structure containing atleast one heteroatom selected from the group consisting of O, N and S,optionally containing one to three additional heteroatoms independentlyselected from the group consisting of O, N and S; or a nine or tenmembered bicyclic aromatic ring structure containing at least oneheteroatom selected from the group consisting of O, N and S, optionallycontaining one to four additional heteroatoms independently selectedfrom the group consisting of O, N and S. The heteroaryl group may beattached at any heteroatom or carbon atom of the ring such that theresult is a stable structure.

Examples of suitable heteroaryl groups include, but are not limited to,pyrrolyl, furyl, thienyl, oxazolyl, imidazolyl, purazolyl, isoxazolyl,isothiazolyl, triazolyl, thiadiazolyl, pyridyl, pyridazinyl,pyrimidinyl, pyrazinyl, pyranyl, furazanyl, indolizinyl, indolyl,isoindolinyl, indazolyl, benzofuryl, benzothienyl, benzimidazolyl,benzthiazolyl, purinyl, quinolizinyl, quinolinyl, isoquinolinyl,isothiazolyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl,naphthyridinyl, pteridinyl, and the like. Preferred heteroaryl groupsinclude pyrrolyl, pyridyl, pyrazolyl, pyrazinyl, and the like.

As used herein, the notation “*” shall denote the presence of astereogenic center.

When a particular group is “substituted” (e.g., aryl, heterocycloalkyl,heteroaryl), that group may have one or more substituents, preferablyfrom one to five substituents, more preferably from one to threesubstituents, most preferably from one to two substituents,independently selected from the list of substituents.

With reference to substituents, the term “independently” means that whenmore than one of such substituents is possible, such substituents may bethe same or different from each other.

To provide a more concise description, some of the quantitativeexpressions given herein are not qualified with the term “about”. It isunderstood that whether the term “about” is used explicitly or not,every quantity given herein is meant to refer to the actual given value,and it is also meant to refer to the approximation to such given valuethat would reasonably be inferred based on the ordinary skill in theart, including approximations due to the experimental and/or measurementconditions for such given value.

As used herein, unless otherwise noted, the term “leaving group” shallmean a charged or uncharged atom or group which departs during asubstitution or displacement reaction. Suitable examples include, butare not limited to, Br, Cl, I, mesylate, tosylate, and the like.

As used herein, unless otherwise noted, the term “nitrogen protectinggroup” shall mean a group which may be attached to a nitrogen atom toprotect said nitrogen atom from participating in a reaction and whichmay be readily removed following the reaction. Suitable nitrogenprotecting groups include, but are not limited to carbamates—groups ofthe formula —C(O)O—R wherein R is for example methyl, ethyl, t-butyl,benzyl, phenylethyl, CH₂═CH—CH₂—, and the like; amides—groups of theformula —C(O)—R′ wherein R′ is for example methyl, phenyl,trifluoromethyl, and the like; N-sulfonyl derivatives—groups of theformula —SO₂—R″ wherein R″ is for example tolyl, phenyl,trifluoromethyl, 2,2,5,7,8-pentamethylchroman-6-yl-,2,3,6-trimethyl-4-methoxybenzene, and the like. Other suitable nitrogenprotecting groups may be found in texts such as T. W. Greene & P. G. M.Wuts, Protective Groups in Organic Synthesis, John Wiley & Sons, 1991.

Under standard nomenclature used throughout this disclosure, theterminal portion of the designated side chain is described first,followed by the adjacent functionality toward the point of attachment.Thus, for example, a “phenyl-alkyl-amino-carbonyl-alkyl” substituentrefers to a group of the formula

Abbreviations used in the specification, particularly the Schemes andExamples, are as follows

-   -   DIPEA=Diethylisopropylamine    -   DMF=N,N-Dimethylformamide    -   HEPES=4-(2-Hydroxyethyl)-1-Piperizine Ethane Sulfonic Acid    -   HPLC=High Pressure Liquid Chromatography    -   LiHMDS=Lithium Hexamethyldisilazinamide    -   MOM=Methoxy methyl    -   MOM-Br=Methoxy methyl bromide    -   MOM-Cl=Methoxy methyl chloride    -   Pd(PPh₃)₄ Palladium Tetrakis(triphenylphosphine)    -   SEM=2-(Trimethylsilyl)ethoxy methyl    -   SEM-Cl=2-(Trimethylsilyl)ethoxy methyl chloride    -   TEA or Et₃N=Triethylamine    -   Tf=Triflate (i.e. —SO₂—CF₃)    -   Tf₂O=Triflic anhydride    -   THF=Tetrahydrofuran

The term “subject” as used herein, refers to an animal, preferably amammal, most preferably a human, who has been the object of treatment,observation or experiment.

The term “therapeutically effective amount” as used herein, means thatamount of active compound or pharmaceutical agent that elicits thebiological or medicinal response in a tissue system, animal or humanthat is being sought by a researcher, veterinarian, medical doctor orother clinician, which includes alleviation of the symptoms of thedisease or disorder being treated.

As used herein, the term “composition” is intended to encompass aproduct comprising the specified ingredients in the specified amounts,as well as any product which results, directly or indirectly, fromcombinations of the specified ingredients in the specified amounts.

Where the compounds according to this invention have at least one chiralcenter, they may accordingly exist as enantiomers. Where the compoundspossess two or more chiral centers, they may additionally exist asdiastereomers. It is to be understood that all such isomers and mixturesthereof are encompassed within the scope of the present invention.Furthermore, some of the crystalline forms for the compounds may existas polymorphs and as such are intended to be included in the presentinvention. In addition, some of the compounds may form solvates withwater (i.e., hydrates) or common organic solvents, and such solvates arealso intended to be encompassed within the scope of this invention.

One skilled in the art will recognize that wherein a reaction step ofthe present invention may be carried out in a variety of solvents orsolvent systems, said reaction step may also be carried out in a mixtureof the suitable solvents or solvent systems.

Where the processes for the preparation of the compounds according tothe invention give rise to mixture of stereoisomers, these isomers maybe separated by conventional techniques such as preparativechromatography. The compounds may be prepared in racemic form, orindividual enantiomers may be prepared either by enantiospecificsynthesis or by resolution. The compounds may, for example, be resolvedinto their component enantiomers by standard techniques, such as theformation of diastereomeric pairs by salt formation with an opticallyactive acid, such as (−)-di-p-toluoyl-D-tartaric acid and/or(+)-di-p-toluoyl-L-tartaric acid followed by fractional crystallizationand regeneration of the free base. The compounds may also be resolved byformation of diastereomeric esters or amides, followed bychromatographic separation and removal of the chiral auxiliary.Alternatively, the compounds may be resolved using a chiral HPLC column.

During any of the processes for preparation of the compounds of thepresent invention, it may be necessary and/or desirable to protectsensitive or reactive groups on any of the molecules concerned. This maybe achieved by means of conventional protecting groups, such as thosedescribed in Protective Groups in Organic Chemistry, ed. J. F. W.McOmie, Plenum Press, 1973; and T. W. Greene & P. G. M. Wuts, ProtectiveGroups in Organic Synthesis, John Wiley & Sons, 1991. The protectinggroups may be removed at a convenient subsequent stage using methodsknown from the art.

The present invention includes within its scope prodrugs of thecompounds of this invention. In general, such prodrugs will befunctional derivatives of the compounds which are readily convertible invivo into the required compound. Thus, in the methods of treatment ofthe present invention, the term “administering” shall encompass thetreatment of the various disorders described with the compoundspecifically disclosed or with a compound which may not be specificallydisclosed, but which converts to the specified compound in vivo afteradministration to the patient. Conventional procedures for the selectionand preparation of suitable prodrug derivatives are described, forexample, in “Design of Prodrugs”, ed. H. Bundgaard, Elsevier, 1985.

For use in medicine, the salts of the compounds of this invention referto non-toxic “pharmaceutically acceptable salts.” Other salts may,however, be useful in the preparation of compounds according to thisinvention or of their pharmaceutically acceptable salts. Suitablepharmaceutically acceptable salts of the compounds include acid additionsalts which may, for example, be formed by mixing a solution of thecompound with a solution of a pharmaceutically acceptable acid such ashydrochloric acid, sulfuric acid, fumaric acid, maleic acid, succinicacid, acetic acid, benzoic acid, citric acid, tartaric acid, carbonicacid or phosphoric acid. Furthermore, where the compounds of theinvention carry an acidic moiety, suitable pharmaceutically acceptablesalts thereof may include alkali metal salts, e.g., sodium or potassiumsalts; alkaline earth metal salts, e.g., calcium or magnesium salts; andsalts formed with suitable organic ligands, e.g., quaternary ammoniumsalts. Thus, representative pharmaceutically acceptable salts includethe following:

acetate, benzenesulfonate, benzoate, bicarbonate, bisulfate, bitartrate,borate, bromide, calcium edetate, camsylate, carbonate, chloride,clavulanate, citrate, dihydrochloride, edetate, edisylate, estolate,esylate, fumarate, gluceptate, gluconate, glutamate,glycollylarsanilate, hexylresorcinate, hydrabamine, hydrobromide,hydrochloride, hydroxynaphthoate, iodide, isothionate, lactate,lactobionate, laurate, malate, maleate, mandelate, mesylate,methylbromide, methylnitrate, methylsulfate, mucate, napsylate, nitrate,N-methylglucamine ammonium salt, oleate, pamoate (embonate), palmitate,pantothenate, phosphate/diphosphate, polygalacturonate, salicylate,stearate, sulfate, subacetate, succinate, tannate, tartrate, teoclate,tosylate, triethiodide and valerate.

Representative acids and bases which may be used in the preparation ofpharmaceutically acceptable salts include the following:

acids including acetic acid, 2,2-dichloroactic acid, acylated aminoacids, adipic acid, alginic acid, ascorbic acid, L-aspartic acid,benzenesulfonic acid, benzoic acid, 4-acetamidobenzoic acid,(+)-camphoric acid, camphorsulfonic acid, (+)-(1S)-camphor-10-sulfonicacid, capric acid, caproic acid, caprylic acid, cinnamic acid, citricacid, cyclamic acid, dodecylsulfuric acid, ethane-1,2-disulfonic acid,ethanesulfonic acid, 2-hydrocy-ethanesulfonic acid, formic acid, fumaricacid, galactaric acid, gentisic acid, glucoheptonic acid, D-gluconicacid, D-glucoronic acid, L-glutamic acid, α-oxo-glutaric acid, glycolicacid, hipuric acid, hydrobromic acid, hydrochloric acid, (+)-L-lacticacid, (±)-DL-lactic acid, lactobionic acid, maleic acid, (−)-L-malicacid, malonic acid, (±)-DL-mandelic acid, methanesulfonic acid,naphthalene-2-sulfonic acid, naphthalene-1,5-disulfonic acid,1-hydroxy-2-naphthoic acid, nicotinc acid, nitric acid, oleic acid,orotic acid, oxalic acid, palmitric acid, pamoic acid, phosphoric acid,L-pyroglutamic acid, salicylic acid, 4-amino-salicylic acid, sebaicacid, stearic acid, succinic acid, sulfuric acid, tannic acid,(+)-L-tartaric acid, thiocyanic acid, p-toluenesulfonic acid andundecylenic acid; and

bases including ammonia, L-arginine, benethamine, benzathine, calciumhydroxide, choline, deanol, diethanolamine, diethylamine,2-(diethylamino)-ethanol, ethanolamine, ethylenediamine,N-methyl-glucamine, hydrabamine, 1H-imidazole, L-lysine, magnesiumhydroxide, 4-(2-hydroxyethyl)-morpholine, piperazine, potassiumhydroxide, 1-(2-hydroxyethyl)-pyrrolidine, secondary amine, sodiumhydroxide, triethanolamine, tromethamine and zinc hydroxide.

Compounds of formula (I) may be prepared according to the processoutlined in Scheme 1. More particularly, Scheme 1 outlines a process forattaching the -(L¹)_(a)-R³ and/or R⁴ groups.

Accordingly, a suitably substituted compound of formula (X), a knowncompound or compound prepared by known methods, is reacted with asuitably substituted electrophile, designated as E¹, for example R³—CHO,R⁴—CHO, R³—C(O)—Cl, R⁴—C(O)—Cl, R³—N═C═O, MOM-Cl, MOM-Br, SEM-Cl, andthe like, to yield a mixture of the compounds of formula (XI), (XII) and(XIII), wherein E² is the corresponding substituent group.

For example, the table below lists the substituent group E² which isincorporated into the compounds of formula (XI), X(II) and (XIII) whenthe compound of formula (X) is reacted with the E¹ electrophiles listedabove.

TABLE 2 E¹ (Electrophile) E² (Substituent Group) R³—CHO —CH(OH)—R³R⁴—CHO —CH(OH)—R⁴ R³—C(O)—Cl —C(O)—R³ R⁴—C(O)—Cl —C(O)—R⁴ R³—N═C═O—C(O)—NH—R³ MOM-Cl or MOM-Br MOM SEM-Cl or SEM-Br SEM

One skilled in the art will recognize that depending on the choice ofelectrophile E¹, the compounds of formula (XI), (XII) and/or (XIII) maycorrespond to compounds of formula (I).

Preferably, the mixture of compounds of formula (XI), (XII) and (XIII)is separated, according to known methods, for example by columnchromatography.

One skilled in the art will further recognize that compounds of formula(I) wherein the -(L¹)_(a)-R³ and/or R⁴ groups are different may beprepared according to the process outlined in Scheme 1, repeating theprocess as necessary, and selecting and substituting suitablysubstituted starting materials for the compound of formula (X) and theE¹ reactant as appropriate.

One skilled in the art will further recognize that compounds of formula(I) wherein L¹ is present and is —C(O)—NR^(A)— and wherein R^(A) isother than hydrogen may be prepared from the corresponding compound offormula (I) wherein R^(A) is hydrogen by reacting with a suitablyselected alkylating agent, according to known methods.

Compounds of formula (I) wherein R⁴ is selected from aryl or a6-membered heteroaryl group are similarly prepared according to theprocess outlined in Scheme 1 above, substituting a suitably substitutedcompound of formula (XIV)

for the compound of formula (X).

Compounds of formula (X) or compounds of formula (I) wherein R¹ and/orR² are selected from —O—SO₂—CF₃ or CN may be prepared from thecorresponding compound of formula (X) or compound of formula (I) whereinthe corresponding R¹ and/or R² group(s) are OH, as outlined in Scheme 2.For illustration purposes. Scheme 2 is shown as the process would beapplied to the representative compound of formula (Ia).

Accordingly, a suitably substituted compound of formula (Ia), a knowncompound or compound prepared by known methods, is reacted with triflateanhydride, a known compound, in the presence of a tertiary amine basesuch as TEA, DIPEA, pyridine, and the like, preferably pyridine, in anorganic solvent such as methylene chloride, chloroform, and the like, toyield the corresponding compound of formula (Ib).

The compound of formula (Ib) is reacted with Zn(CN)₂, sodium cyanide,potassium cyanide and the like, in an organic solvent such as DMF, THF,toluene, and the like, at an elevated temperature in the range of about60° C. to about 150° C., to yield the corresponding compound of formula(Ic).

Compounds of formula (I) wherein -L¹-R³ is allyl may be preparedaccording to the process outlined in Scheme 3.

More specifically, a suitably substituted compound of formula (XV), aknown compound or compound prepared by known methods, is reactedaccording to known methods (for example by subjecting to heat) to yieldthe corresponding compound of formula (Id).

The present invention further comprises pharmaceutical compositionscontaining one or more compounds of formula (I) with a pharmaceuticallyacceptable carrier. Pharmaceutical compositions containing one or moreof the compounds of the invention described herein as the activeingredient can be prepared by intimately mixing the compound orcompounds with a pharmaceutical carrier according to conventionalpharmaceutical compounding techniques. The carrier may take a widevariety of forms depending upon the desired route of administration(e.g., oral, parenteral). Thus for liquid oral preparations such assuspensions, elixirs and solutions, suitable carriers and additivesinclude water, glycols, oils, alcohols, flavoring agents, preservatives,stabilizers, coloring agents and the like; for solid oral preparations,such as powders, capsules and tablets, suitable carriers and additivesinclude starches, sugars, diluents, granulating agents, lubricants,binders, disintegrating agents and the like. Solid oral preparations mayalso be coated with substances such as sugars or be enteric-coated so asto modulate major site of absorption. For parenteral administration, thecarrier will usually consist of sterile water and other ingredients maybe added to increase solubility or preservation. Injectable suspensionsor solutions may also be prepared utilizing aqueous carriers along withappropriate additives.

To prepare the pharmaceutical compositions of this invention, one ormore of the compounds of the present invention selected as the activeingredient is intimately admixed with a pharmaceutical carrier accordingto conventional pharmaceutical compounding techniques, which carrier maytake a wide variety of forms depending of the form of preparationdesired for administration, e.g., oral or parenteral such asintramuscular. In preparing the compositions in oral dosage form, any ofthe usual pharmaceutical media may be employed. Thus, for liquid oralpreparations, such as for example, suspensions, elixirs and solutions,suitable carriers and additives include water, glycols, oils, alcohols,flavoring agents, preservatives, coloring agents and the like; for solidoral preparations such as, for example, powders, capsules, caplets,gelcaps and tablets, suitable carriers and additives include starches,sugars, diluents, granulating agents, lubricants, binders,disintegrating agents and the like. Because of their ease inadministration, tablets and capsules represent the most advantageousoral dosage unit form, in which case solid pharmaceutical carriers areobviously employed. If desired, tablets may be sugar coated or entericcoated by standard techniques. For parenterals, the carrier will usuallycomprise sterile water, through other ingredients, for example, forpurposes such as aiding solubility or for preservation, may be included.Injectable suspensions may also be prepared, in which case appropriateliquid carriers, suspending agents and the like may be employed. Thepharmaceutical compositions herein will contain, per dosage unit, e.g.,tablet, capsule, powder, injection, teaspoonful and the like, an amountof the active ingredient necessary to deliver an effective dose asdescribed above. The pharmaceutical compositions herein will contain,per unit dosage unit, e.g., tablet, capsule, powder, injection,suppository, teaspoonful and the like, of from about 50-100 mg and maybe given at a dosage of from about 0.5-5.0 mg/kg/day, preferably fromabout 1.0-3.0 mg/kg/day. The dosages, however, may be varied dependingupon the requirement of the patients, the severity of the conditionbeing treated and the compound being employed. The use of either dailyadministration or post-periodic dosing may be employed.

Preferably these compositions are in unit dosage forms from such astablets, pills, capsules, powders, granules, sterile parenteralsolutions or suspensions, metered aerosol or liquid sprays, drops,ampoules, autoinjector devices or suppositories; for oral parenteral,intranasal, sublingual or rectal administration, or for administrationby inhalation or insufflation. Alternatively, the composition may bepresented in a form suitable for once-weekly or once-monthlyadministration; for example, an insoluble salt of the active compound,such as the decanoate salt, may be adapted to provide a depotpreparation for intramuscular injection. For preparing solidcompositions such as tablets, the principal active ingredient is mixedwith a pharmaceutical carrier, e.g. conventional tableting ingredientssuch as corn starch, lactose, sucrose, sorbitol, talc, stearic acid,magnesium stearate, dicalcium phosphate or gums, and otherpharmaceutical diluents, e.g. water, to form a solid preformulationcomposition containing a homogeneous mixture of a compound of thepresent invention, or a pharmaceutically acceptable salt thereof. Whenreferring to these preformulation compositions as homogeneous, it ismeant that the active ingredient is dispersed evenly throughout thecomposition so that the composition may be readily subdivided intoequally effective dosage forms such as tablets, pills and capsules. Thissolid preformulation composition is then subdivided into unit dosageforms of the type described above containing from 0.1 to about 500 mg ofthe active ingredient of the present invention. The tablets or pills ofthe novel composition can be coated or otherwise compounded to provide adosage form affording the advantage of prolonged action. For example,the tablet or pill can comprise an inner dosage and an outer dosagecomponent, the latter being in the form of an envelope over the former.The two components can be separated by an enteric layer which serves toresist disintegration in the stomach and permits the inner component topass intact into the duodenum or to be delayed in release. A variety ofmaterial can be used for such enteric layers or coatings, such materialsincluding a number of polymeric acids with such materials as shellac,cetyl alcohol and cellulose acetate.

The liquid forms in which the novel compositions of the presentinvention may be incorporated for administration orally or by injectioninclude, aqueous solutions, suitably flavored syrups, aqueous or oilsuspensions, and flavored emulsions with edible oils such as cottonseedoil, sesame oil, coconut oil or peanut oil, as well as elixirs andsimilar pharmaceutical vehicles. Suitable dispersing or suspendingagents for aqueous suspensions, include synthetic and natural gums suchas tragacanth, acacia, alginate, dextran, sodium carboxymethylcellulose,methylcellulose, polyvinyl-pyrrolidone or gelatin.

The method of treating disorders related to ion channels, for examplepotassium ion channels, described in the present invention may also becarried out using a pharmaceutical composition comprising any of thecompounds as defined herein and a pharmaceutically acceptable carrier.The pharmaceutical composition may contain between about 0.01 mg and1000 mg, preferably about 1 to 500 mg, more preferably, 10 to 100 mg ofthe compound, and may be constituted into any form suitable for the modeof administration selected. Carriers include necessary and inertpharmaceutical excipients, including, but not limited to, binders,suspending agents, lubricants, flavorants, sweeteners, preservatives,dyes, and coatings. Compositions suitable for oral administrationinclude solid forms, such as pills, tablets, caplets, capsules (eachincluding immediate release, timed release and sustained releaseformulations), granules, and powders, and liquid forms, such assolutions, syrups, elixers, emulsions, and suspensions. Forms useful forparenteral administration include sterile solutions, emulsions andsuspensions.

Advantageously, compounds of the present invention may be administeredin a single daily dose, or the total daily dosage may be administered individed doses of two, three or four times daily. Furthermore, compoundsfor the present invention can be administered in intranasal form viatopical use of suitable intranasal vehicles, or via transdermal skinpatches well known to those of ordinary skill in that art. To beadministered in the form of a transdermal delivery system, the dosageadministration will, of course, be continuous rather than intermittentthroughout the dosage regimen.

For instance, for oral administration in the form of a tablet orcapsule, the active drug component can be combined with an oral,non-toxic pharmaceutically acceptable inert carrier such as ethanol,glycerol, water and the like. Moreover, when desired or necessary,suitable binders; lubricants, disintegrating agents and coloring agentscan also be incorporated into the mixture. Suitable binders include,without limitation, starch, gelatin, natural sugars such as glucose orbeta-lactose, corn sweeteners, natural and synthetic gums such asacacia, tragacanth or sodium oleate, sodium stearate, magnesiumstearate, sodium benzoate, sodium acetate, sodium chloride and the like.Disintegrators include, without limitation, starch, methyl cellulose,agar, bentonite, xanthan gum and the like.

The liquid forms in suitably flavored suspending or dispersing agentssuch as the synthetic and natural gums, for example, tragacanth, acacia,methylcellulose and the like. For parenteral administration, sterilesuspensions and solutions are desired. Isotonic preparations whichgenerally contain suitable preservatives are employed when intravenousadministration is desired.

The compound of the present invention can also be administered in theform of liposome delivery systems, such as small unilamellar vesicles,large unilamellar vesicles, and multilamellar vesicles. Liposomes can beformed from a variety of phospholipids, such as cholesterol,stearylamine or phophatidylcholines.

Compounds of the present invention may also be delivered by the use ofmonoclonal antibodies as individual carriers to which the compoundmolecules are coupled. The compounds of the present invention may alsobe coupled with soluble polymers as targetable drug carriers. Suchpolymers can include polyvinylpyrrolidone, pyran copolymer,polyhydroxypropylmethacrylamidephenol,polyhydroxy-ethylaspartamidephenol, or polyethyl eneoxidepolylysinesubstituted with palmitoyl residue. Furthermore, the compounds of thepresent invention may be coupled to a class of biodegradable polymersuseful in achieving controlled release of a drug, for example,polylactic acid, polyepsilon caprolactone, polyhydroxy butyeric acid,polyorthoesters, polyacetals, polydihydropyrans, polycyanoacrylates andcross-linked or amphipathic block copolymers of hydrogels.

Compounds of this invention may be administered in any of the foregoingcompositions and according to dosage regimens established in the artwhenever treatment of disorders related to ion channels, for examplepotassium ion channels, is required.

The daily dosage of the products may be varied over a wide range from0.01 to 1,000 mg per adult human per day. For oral administration, thecompositions are preferably provided in the form of tablets containing,0.01, 0.05, 0.1, 0.5, 1.0, 2.5, 5.0, 10.0, 15.0, 25.0, 50.0, 100, 150,200, 250, 500 and 1000 milligrams of the active ingredient for thesymptomatic adjustment of the dosage to the patient to be treated. Aneffective amount of the drug is ordinarily supplied at a dosage level offrom about 0.01 mg/kg to about 300 mg/kg of body weight per day.Preferably, the range is from about 0.5 to about 5.0 mg/kg of bodyweight per day, most preferably, from about 1.0 to about 3.0 mg/kg ofbody weight per day. The compounds may be administered on a regimen of 1to 4 times per day.

Optimal dosages to be administered may be readily determined by thoseskilled in the art, and will vary with the particular compound used, themode of administration, the strength of the preparation, the mode ofadministration, and the advancement of the disease condition. Inaddition, factors associated with the particular patient being treated,including patient age, weight, diet and time of administration, willresult in the need to adjust dosages.

The following Examples are set forth to aid in the understanding of theinvention, and are not intended and should not be construed to limit inany way the invention set forth in the claims which follow thereafter.

Example 1 Trifluoro-methanesulfonic acid3-(2,4-dimethoxy-phenyl)-4-(2-methoxy-ethyl)-2-oxo-2H-chromen-7-yl ester(Compound #2)

3-(2,4-Dimethoxy-phenyl)-7-hydroxy-4-(2-methoxy-ethyl)-chromen-2-one(1.8 g, 5.2 mmol) and pyridine (30 mL) were dissolved in CH₂Cl₂ (200 mL)at room temperature and the reaction mixture was cooled to 0° C., thentreated with Tf₂O (1.3 mL). After 1 hour, ethyl acetate (200 mL) waspoured into the reaction mixture and the reaction mixture wastransferred into a separation funnel. The reaction mixture was thenwashed with 5% sodium bicarbonate (2×250 ml), water (250 ml) and thenbrine. The organic layer was dried over sodium sulfate and concentrated.Flash column chromatography on silica gel eluted with 20-50% ethylacetate in hexane yielded the title compound as a yellow solid.

m/z=489 (M+H⁺)

Example 24-[2-(4-Chloro-phenyl)-2-oxo-ethyl]-2-oxo-2H-chromene-7-carbonitrile(Compound #4) and3-(4-Chloro-benzoyl)-4-methyl-2-oxo-2H-chromene-7-carbonitrile (Compound#3)

To a solution of 4-methyl-2-oxo-2H-chromene-7-carbonitrile (170 mg,0.918 mmol) in dry THF (5 mL) at −20° C. was added drop wise 1.0 MLiHMDS solution in THF (1 mL). After 30 minutes 4-chloro-benzoylchloride (160 μL) was added slowly and the reaction mixture was stirredfor 1 hour. The reaction mixture was then quenched with saturatedaqueous ammonium chloride (10 mL) and extracted with ethyl acetate (50mL). The organic layer was separated and dried over sodium sulfate, thenconcentrated and purified on silica gel eluted with 30% ethyl acetate inhexanes to yield the title compounds as a white foam and a white solid,respectively.

4-[2-(4-Chloro-phenyl)-2-oxo-ethyl]-2-oxo-2H-chromene-7-carbonitrile

m/z=324 (M+H+)

3-(4-Chloro-benzoyl)-4-methyl-2-oxo-2H-chromene-7-carbonitrile

m/z=324 (M+H+)

¹HNMR (CDCl₃, 400 MHz) δ (ppm) 7.8 (m, 2H), 7.65 (s, 1H), 7.8 (d, J=8.4Hz, 1H), 7.4 (d, J=8.4 Hz, 2H), 6.3 (dd, ¹J=8.4 Hz, ²J=2 Hz, 1H), 2.4(s, 3H).

Example 33-(2,4-Dimethoxy-phenyl)-4-(2-methoxy-ethyl)-2-oxo-2H-chromene-7-carbonitrile(Compound #6)

Trifluoro-methanesulfonic acid3-(2,4-dimethoxy-phenyl)-4-(2-methoxy-ethyl)-2-oxo-2H-chromen-7-yl ester(862 mg, 1.766 mol), Zn (CN)₂ (310 mg) and Pd(PPh₃)₄ (204 mg) weredissolved in DMF (12 mL) at room temperature in a sealed tube. After 10min, the reaction mixture was heated to 150° C. for 4 h. The reactionmixture was cooled to room temperature and ethyl acetate (200 mL) wasadded. The reaction mixture was then poured into a separation funnel,washed with water (2×100 ml) and brine (2×100 ml). The organic layer wasdried over sodium sulfate and concentrated. The product was purified onsilica gel eluted with 30-50% ethyl acetate in hexanes to yield3-(2,4-Dimethoxy-phenyl)-4-(2-methoxy-ethyl)-2-oxo-2H-chromene-7-carbonitrileas a slightly yellow solid.

M/z=489 (M+H+)

¹HNMR (CDCl₃, 400 MHz) δ (ppm) 7.85 (d, J=6.0 Hz, 1H), 7.65 (s, 1H),7.55 (d, J=6.0 Hz, 1H), 7.1 (d, J=6.1 Hz, 1H), 6.5 (m, 2H), 3.85 (s,3H), 3.75 (s, 3H), 3.43 (m, 2H), 2.95 (m, 2H).

Example 4 Trifluoro-methanesulfonic acid3-(2,4-dihydroxy-phenyl)-4-(2-hydroxy-ethyl)-2-oxo-2H-chromen-7-yl ester(Compound #7)

Trifluoro-methanesulfonic acid3-(2,4-dimethoxy-phenyl)-4-(2-methoxy-ethyl)-2-oxo-2H-chromen-7-yl ester(450 mg, 0.92 mol) was dissolved in CH₂Cl₂ (10 mL) at room temperaturein a 200 ml round bottom flask. The reaction mixture was then cooled to−30° C., and BBr₃ (1.8 ml) was added and the reaction mixture stirred atroom temperature for 4 h. The reaction mixture was cooled to 0° C. andwater (40 mL) was added, followed by ethyl acetate (50 mL). The reactionmixture was then poured into a separation funnel. The organic layer wasseparated and washed with water (1×40 ml) and brine (1×30 ml). Theorganic layer was dried over sodium sulfate and concentrated. Theproduct was purified on silica gel eluted with 50%-100% ethyl acetate inhexanes to yield trifluoro-methanesulfonic acid3-(2,4-dihydroxy-phenyl)-4-(2-hydroxy-ethyl)-2-oxo-2H-chromen-7-yl esteras a light yellow foam

M/z=447 (M+H+), 469 (M+Na)

¹HNMR (CDCl₃, 400 MHz) δ (ppm) 7.91 (d, J=6.0 Hz, 1H), 7.25-7.35 (m,3H), 6.85 (d, J=6.0 Hz, 1H), 6.4-6.5 (m, 2H), 3.8 (m, 2H), 3.75 (s,2.95-3.2 (m, 5H, 3H exchangeable with D₂O).

Example 53-(2,4-Dihydroxy-phenyl)-4-(2-hydroxy-ethyl)-2-oxo-2H-chromene-7-carbonitrile(Compound #8) and3-(2,4-Dihydroxy-phenyl)-2-oxo-4-vinyl-2H-chromene-7-carbonitrile(Compound #9)

3-(2,4-Dimethoxy-phenyl)-4-(2-methoxy-ethyl)-2-oxo-2H-chromene-7-carbonitrile(380 mg, 1.04 mmol) was dissolved in CH₂Cl₂ (12 mL) at room temperaturein a 200 ml round bottom flask. The reaction mixture was then cooled to−30° C., and BBr₃ (1.8 ml) was added, then the reaction mixture wasstirred at room temperature for 4 h. The reaction mixture was cooled to0° C. and water (40 mL) was added, followed by ethyl acetate (50 mL).The reaction mixture was then poured into a separation funnel. Theorganic layer separated and washed with water (1×40 ml) and brine (1×30ml). The organic layer was dried over sodium sulfate and concentrated.The product was purified on silica gel eluted with 50%-100% ethylacetate in hexanes to yield the title compounds as a foam and a yellowsolid, respectively.

3-(2,4-Dihydroxy-phenyl)-2-oxo-4-vinyl-2H-chromene-7-carbonitrile

m/z=306 (M+H+)

3-(2,4-Dihydroxy-phenyl)-4-(2-hydroxy-ethyl)-2-oxo-2H-chromene-7-carbonitrile

M/z=324 (M+H⁺)

Example 68-Fluoro-5-oxo-11,12-dihydro-5H-6,13-dioxa-benzo[3,4]cyclohepta[2-a]naphthalene-2-carbonitrileand 44-(7-Fluoro-2-oxo-4-vinyl-2H-chromen-3-yl)-3-hydroxy-benzonitrile(Compound #11)

Trifluoro-methanesulfonic acid8-fluoro-5-oxo-4b,10b,11,12-tetrahydro-5H-6,13-dioxa-benzo[3,4]cyclohepta[1,2-a]naphthalen-2-ylester (450 mg, 1.046 mmol), Zn (CN)₂ (183 mg) and Pd(PPh₃)₄ (120 mg)were dissolved in DMF (12 mL) at room temperature in a sealed tube.After 10 min. the reaction mixture was heated to 150° C. for 4 h. Thereaction mixture was cooled to room temperature and ethyl acetate (200mL) was added. The reaction mixture was then poured into a separationfunnel, washed with water (2×100 ml) and brine (2×100 ml). The organiclayer was dried over sodium sulfate and concentrated. The product waspurified on silica gel eluted with 30-50% ethyl acetate in hexanes toyield the title compounds as a thick yellow oil and as a brownsemi-solid, respectively.

8-Fluoro-5-oxo-4b,10b,11,12-tetrahydro-5H-6,13-dioxa-benzo[3,4]cyclohepta[1,2-a]naphthalene-2-carbonitrile

M/z=310 (M+H+)

¹HNMR (CDCl₃, 400 MHz) δ (ppm) 7.85 (d, J=6.0 Hz, 1H), 7.75-7.55 (m,J=6.0 Hz, 2H), 7.1-7.22 (m, J=6.1 Hz, 3H), 4.75 (t, 2H), 3.05 (t, 3H)

4-(7-Fluoro-2-oxo-4-vinyl-chroman-3-yl)-3-hydroxy-benzonitrile

M/z=310 (M+H+)

¹HNMR (CDCl₃, 400 MHz) δ (ppm) 7.83 (m, 2H), 7.1-7.3 (m, 4H), 6.5 (dd,J=8 Hz, 6 Hz, 1H), 6.25 (bs, 1H), 5.6 (d, J=10 Hz, 1H), 5.4 (d, J=10 Hz,1H).

Example 7 Trifluoro-methanesulfonic acid4-[2-(2,4-dichloro-phenyl)-2-hydroxy-ethyl]-2-oxo-2H-chromen-7-yl ester(Compound #12)

To a solution of Trifluoro-methanesulfonic acid4-methyl-2-oxo-2H-chromen-7-yl ester (340 mg, 1.1 mmol) in dry THF (8mL0 at −20° C. was added drop wise 1.0 M LiHMDS solution in THF (1.2mL). After 30 minutes 2,4-dichloro-benzaldehyde (130 μL) was addedslowly into the reaction mixture and the reaction mixture was stirredfor 1 hour. The reaction mixture was quenched with saturated aqueousammonium chloride (10 mL) and extracted with ethyl acetate (50 mL). Theorganic layer was separated and dried over sodium sulfate, concentratedand purified on silica gel eluted with 30% ethyl acetate in hexanes toyield trifluoro-methanesulfonic acid4-[2-(2,4-dichloro-phenyl)-2-hydroxy-ethyl]-2-oxo-2H-chromen-7-yl esteras a light yellow solid.

m/z 484 (M+H+)

¹ HNMR (CDCl₃, 400 MHz) δ (ppm) 7.9 (d, J=6 Hz, 1H), 7.6 Hz (d, J=6 Hz,1H), 7.1-7.4 (m, 4H), 6.45 (s, 1H), 5.45 (m, 1H), 2.95-3.1 (m, 2H).

Example 84-[2-(2,4-Dichloro-phenyl)-2-hydroxy-ethyl]-2-oxo-2H-chromene-7-carbonitrile(Compound #14)

To a solution of 4-methyl-2-oxo-2H-chromene-7-carbonitrile (76 mg, 0.427mmol) in dry THF (4 mL) at −20° C. was added drop wise 1.0 M LiHMDSsolution in THF (0.52 mL). After 30 minutes 2,4-dichloro-benzaldehyde(60 μL) was added slowly into the reaction mixture and then stirred for1 hour. The reaction mixture was then quenched with saturated aqueousammonium chloride (2 mL) and extracted with ethyl acetate (50 mL). Theorganic layer was separated and dried over sodium sulfate, thenconcentrated and purified on silica gel eluted with 30% ethyl acetate inhexanes to yield4-[2-(2,4-dichloro-phenyl)-2-hydroxy-ethyl]-2-oxo-2H-chromene-7-carbonitrileas a yellow solid.

m/z 382 (M+Na+)

¹ HNMR (CDCl₃, 400 MHz) δ (ppm) 7.8 (d, J=6.6 Hz, 1H), 7.3-7.7 Hz (m,5H), 6.55 (s, 1H), 5.42 (m, 1H), 2.85-3.1 (m, 2H).

Example 92-(7-Cyano-2-oxo-2H-chromen-4-yl)-N-(2,4-difluoro-phenyl)-acetamide(Compound #15)

To a solution of 4-methyl-2-oxo-2H-chromene-7-carbonitrile (671 mg, 3.62 mmol) in dry THF (30 mL) at −20° C. was added drop wise 1.0 M LiHMDSsolution in THF (5.4 mL). After 30 minutes2,4-difluoro-1-isocyanato-benzene (224 mg) was added into the reactionmixture and the reaction mixture was then stirred for 1 hour. Thereaction mixture was quenched with saturated aqueous ammonium chloride(25 mL) and extracted with ethyl acetate (50 mL). The organic layer wasseparated and dried over sodium sulfate, then concentrated and purifiedon silica gel eluted with 30%-100% ethyl acetate in hexanes to yield2-(7-cyano-2-oxo-2H-chromen-4-yl)-N-(2,4-difluoro-phenyl)-acetamide as ayellow solid.

M/z=341 (M+H+) 363 (M+Na+)

¹ HNMR (DMSO, 400 MHz) δ (ppm) 10.6 (bs, 1H), 7.65 (s, 1H), 7.52 (d,J=8.1 Hz, 1H), 7.45 (m, 1H), 6.8-7.25 (m, 3H), 6.45 (s, 1H), 3.72(bs2H).

Example 102-(7-Cyano-2-oxo-2H-chromen-4-yl)-N-(2-fluoro-phenyl)-acetamide(Compound #16)

To a solution of 4-methyl-2-oxo-2H-chromene-7-carbonitrile (670 mg, 3.6mmol) in dry THF (30 mL) at −20° C. was added drop wise 1.0 M LiHMDSsolution in THF (5.4 mL). After 30 minutes 2-fluoro-1-isocyanato-benzene(189 mg) was added into the reaction mixture and the reaction mixturewas stirred for 1 hour. The reaction mixture was then quenched withsaturated aqueous ammonium chloride (25 mL) and extracted with ethylacetate (50 mL). The organic layer was separated and dried over sodiumsulfate, then concentrated and purified on silica gel eluted with30%-100% ethyl acetate in hexanes to yield2-(7-cyano-2-oxo-2H-chromen-4-yl)-N-(2-fluoro-phenyl)-acetamide as asolid.

M/z=323 (M+H+).

¹ HNMR (CDCl₃, 400 MHz) δ (ppm) 11.2 (bs, 1H), 7.7 (s, 1H), 7.5-7.1 (m,5H), 6.35 (s, 1H), 3.81 (bs, 2H).

Example 11N-(3-Chloro-phenyl)-2-(7-cyano-2-oxo-2H-chromen-4-yl)-acetamide(Compound #18)

To a solution of 4-methyl-2-oxo-2H-chromene-7-carbonitrile (673 mg, 3. 6mmol) in dry THF (30 mL) at −20° C. was added drop wise 1.0 M LiHMDSsolution in THF (5.4 mL). After 30 minutes 3-chloro-1-isocyanato-benzene(222.3 mg) was added into the reaction mixture and the reaction mixturewas stirred for 1 hour. The reaction mixture was then quenched withsaturated aqueous ammonium chloride (25 mL) and extracted with ethylacetate (50 mL). The organic layer was separated and dried over sodiumsulfate, then concentrated and purified on silica gel eluted with30%-100% ethyl acetate in hexanes to yield2-(7-cyano-2-oxo-2H-chromen-4-yl)-N-(3-chloro-phenyl)-acetamide as ayellow solid.

M/z=339 (M+H⁺) 361 (M+Na⁺).

Example 12N-(2-Chloro-phenyl)-2-(7-cyano-2-oxo-2H-chromen-4-yl)-acetamide(Compound #17)

To a solution of 4-methyl-2-oxo-2H-chromene-7-carbonitrile (670 mg, 3.6mmol) in dry THF (30 mL) at −20° C. was added drop wise 1.0 M LiHMDSsolution in THF (5.4 mL). After 30 minutes 2-chloro-1-isocyanato-benzene(221 mg) was added into the reaction mixture and the reaction mixturewas stirred for 1 hour. The reaction mixture was then quenched withsaturated aqueous ammonium chloride (25 mL) and extracted with ethylacetate (50 mL). The organic layer was separated and dried over sodiumsulfate, then concentrated and purified on silica gel eluted with30%-100% ethyl acetate in hexanes to yield2-(7-cyano-2-oxo-2H-chromen-4-yl)-N-(2-chloro-phenyl)-acetamide as afoam.

M/z=339 (M+H⁺) 361 (M+Na⁺).

Example 132-(7-Cyano-2-oxo-2H-chromen-4-yl)-N-(2,3-dichloro-phenyl)-acetamide(Compound #19)

To a solution of 4-methyl-2-oxo-2H-chromene-7-carbonitrile (673 mg, 3.6mmol) in dry THF (30 mL) at −20° C. was added drop wise 1.0 M LiHMDSsolution in THF (5.4 mL). After 30 minutes 2-chloro-1-isocyanato-benzene(272 mg) was added into the reaction mixture and the reaction mixturewas stirred for 1 hour. The reaction mixture was then quenched withsaturated aqueous ammonium chloride (25 mL) and extracted with ethylacetate (50 mL). The organic layer was separated and dried over sodiumsulfate, then concentrated and purified on silica gel eluted with30%-100% ethyl acetate in hexanes to yield2-(7-cyano-2-oxo-2H-chromen-4-yl)-N-(2,3-dichloro-phenyl)-acetamide as afoam.

M/z=373 (M+H⁺) 395 (M+Na⁺).

Example 14 Trifluoro-methanesulfonic acid 4-methyl-2-oxo-2H-chromen-6-ylester

6-Hydroxy-4-methyl-chromen-2-one (25 mg, 0.142 mol) and pyridine (300mL) were dissolved in CH₂Cl₂ (200 mL) at room temperature and thereaction mixture was cooled to 0° C. and then treated with Tf₂O (40 mL).After 1 hour, ethyl acetate (900 mL) was poured into the reactionmixture and the reaction mixture was transferred into a separationfunnel. The reaction mixture was then washed with 5% sodium bicarbonate(2×450 ml), water (450 ml) and then brine. The organic layer was driedover sodium sulfate and concentrated. Flash column chromatography onsilica gel eluted with 20-50% ethyl acetate in hexane yielded the titlecompound as a foam.

M/z 309 (M+H⁺)

¹ HNMR (CDCl₃, 400 MHz) δ (ppm) 7.6 (d, J=4 Hz, 1H)), 7.45 (d, J=4 Hz,1H), 7.25 (s, 1H), 6.45 (s, 1H), 2.5 (s, 3H)

Example 15 4-Methyl-2-oxo-2H-chromene-6-carbonitrile

Trifluoro-methanesulfonic acid 4-methyl-2-oxo-2H-chromen-6-yl ester(10.38 mg, 33.7 mmol), Zn (CN)₂ (4.7 g) and Pd(PPh₃)₄ (3.8 g) weredissolved in DMF (200 mL) at room temperature in a sealed tube. After 10min, the reaction mixture was heated to 150° C. for 4 h. The reactionmixture was then cooled to room temperature and ethyl acetate (800 mL)was added. The reaction mixture was then poured into a separationfunnel, washed with water (2×400 ml) and brine (2×600 ml). The organiclayer was dried over sodium sulfate and concentrated. The product waspurified on silica gel eluted with 30-80% ethyl acetate in hexanes toyield 4-methyl-2-oxo-2H-chromene-6-carbonitrile as a white powder.

M/z 186 (M+H⁺)

¹ HNMR (DMSO, 400 MHz) δ (ppm) 8.41 (s, 1H), 8.05 (d, J=6 Hz, 1H), 7.6(d, 6 Hz, 1H), 6.5 (s, 1H). 2.6 (s, 3H)

Example 164-[2-(2,4-Dichloro-phenyl)-2-hydroxy-ethyl]-2-oxo-2H-chromene-6-carbonitrile(Compound #20)

To a solution of 4-methyl-2-oxo-2H-chromene-6-carbonitrile (56 mg, 0.325mmol) in dry THF (12 mL) at −20° C. was added drop wise 1.0 M LiHMDSsolution in THF (0.6 mL). After 30 minutes 2,4-dichlorobenzaldehyde (105mg) was added into the reaction mixture and the reaction mixture wasstirred for 1 hour. The reaction mixture was then quenched withsaturated aqueous ammonium chloride (10 mL) and extracted with ethylacetate (50 mL). The organic layer was separated and dried over sodiumsulfate, then concentrated and purified on silica gel eluted with30%-60% ethyl acetate in hexanes to yield4-[2-(2,4-dichloro-phenyl)-2-hydroxy-ethyl]-2-oxo-2H-chromene-6-carbonitrileas a white powder.

M/z=360 (M+H⁺) 382 (M+Na⁺)

¹ HNMR (DMSO, 400 MHz) δ (ppm) 8.43 (s, 1H), 8.15 (d, J=6 Hz, 1H), 7.7(d, 6 Hz, 1H), 7.65 (m, 2H), 7.50 (d, J=6.2 Hz, 1H), 6.45 (s, 1H). 5.8(d, 1H), 5.24 m, 1H), 3.12 (m, 2H)

Example 174-[2-(3-Chloro-phenyl)-2-oxo-ethyl]-2-oxo-2H-chromene-6-carbonitrile(Compound #21)

To a solution of 4-methyl-2-oxo-2H-chromene-6-carbonitrile (180 mg, 0.92mmol) in dry THF (33 mL) at −20° C. was added drop wise 1.0 M LiHMDSsolution in THF (1.6 mL). After 30 minutes 3-chlorobenzoylchloride (200mg) was added into the reaction mixture and the reaction mixture wasstirred for 1 hour. The reaction mixture was then quenched withsaturated aqueous ammonium chloride (15 mL) and extracted with ethylacetate (50 mL). The organic layer was separated and dried over sodiumsulfate, then concentrated and purified on silica gel eluted with30%-60% ethyl acetate in hexanes to yield4-[2-(3-chloro-phenyl)-2-oxo-ethyl]-2-oxo-2H-chromene-6-carbonitrile asa white solid.

M/z=324 (M+H⁺) 346 (M+Na⁺).

Example 18 Trifluoro-methanesulfonic acid4-[2-(3-chloro-phenyl)-2-oxo-ethyl]-2-oxo-2H-chromen-6-yl ester(Compound #22)

To a solution of 4-methyl-2-oxo-2H-chromene-6-carbonitrile (330 mg, 1.07mmol) in dry THF (33 mL) at −20° C. was added drop wise 1.0 M LiHMDSsolution in THF (1.6 mL). After 30 minutes 3-chlorobenzoylchloride (110mg) was added into the reaction mixture and the reaction mixture stirredfor 1 hour. The reaction mixture was then quenched with saturatedaqueous ammonium chloride (15 mL) and extracted with ethyl acetate (50mL). The organic layer was separated and dried over sodium sulfate, thenconcentrated and purified on silica gel eluted with 30%-60% ethylacetate in hexanes to yield trifluoro-methanesulfonic acid4-[2-(3-Chloro-phenyl)-2-oxo-ethyl]-2-oxo-2H-chromene-6-carbonitrile asa foam.

M/z=447 (M+H⁺) 469 (M+Na⁺)

¹ HNMR (CDCl₃, 400 MHz) δ (ppm) 8.01 (s, 1H), 7.9 (d, J=6 Hz, 1H), 7.61(d, 6 Hz, 1H), 7.2-7.5 (m, 4H), 6.45 (s, 1H). 4.4 (s, 2H)

Example 19 Trifluoro-methanesulfonic acid2-oxo-4-[(2,4,6-trichloro-phenylcarbamoyl)-methyl]-2H-chromen-7-yl ester(Compound #13)

To a solution of trifluoro-methanesulfonic acid4-methyl-2-oxo-2H-chromen-7-yl ester (285 mg, 1.54 mmol) in dry THF (50mL) at −20° C. was added dropwise 1.0 M LiHMDS solution in THF (2.1 mL).After 30 minutes 2,4,5-trichlorophenylisocynate (342 mg) was added intothe reaction mixture and the reaction mixture was stirred for 1 hour.The reaction mixture was then quenched with saturated aqueous ammoniumchloride (32 mL) and extracted with ethyl acetate (50 mL). The organiclayer was separated, dried over sodium sulfate, concentrated andpurified on silica gel eluted with 30%-80% ethyl acetate in hexanes toyield the title compound as a yellow foam.

m/z=529 (M+H+), 551 (M+Na+)

¹ HNMR (CDCl₃, 400 MHz) δ (ppm) 7.9 (d, J=6 Hz, 1H), 7.45 (s, 2H),7.2-7.5 (m, 3H), 6.55 (s, 1H). 3.89 (s, 2H)

Example 20 Potassium Channel Assay

TE671 human medulloblastoma cells were obtained from ATCC and grown inDulbecco's modified Eagle's medium (DMEM) supplemented with 10% fetalbovine serum, 100 U/ml penicillin and 100 U/ml streptomycine.

The day before testing, the cells were plated in black 96-well plates at50K/well. On the day of testing, the growth media was removed, then 100μl of FLIPR buffer (20 mM HEPES, 120 mM NaCl, 2 mM KCl, 2 mM CaCl2, 1 mMMgCl2, 5 mM Glucose) and 100 μl of Membrane Potential Assay Dye(Molecular Devices) dissolved in FLIPR buffer were added to each well.The cells were incubated at room temperature for 15 to 30 min.

The effect of test compounds on KATP channels were evaluated on afluorometric imaging plate reader (FLIPR, Molecular Devices) at roomtemperature. After a baseline period, 50 μl of 5× stock solution of testcompound prepared in FLIPR buffer was added and fluorescent change wasmonitored for 3 minutes. After this reading, glyburide, a KATP channelblocker, was added to a final concentration of 5 μM to check thespecificity of the test compound as a KATP channel openers.Hyperpolarization resulting from KATP channel opening was observed as adecrease in fluorescent intensity.

Representative compounds of the present invention were tested accordingto the procedure described above, with results as listed in Table 3below.

TABLE 3 ID No. EC₅₀ (μM) 2 9.55 3 >30 4 15.87 5 12.21 6 >30 7 19.46 823.22 9 3.29 11 >30 12 6.58 13 8.76 14 >30 15 13.89 16 3.84 17 19.45 187.74 19 10.72 20 >30 21 >30 22 19.90

While the foregoing specification teaches the principles of the presentinvention, with examples provided for the purpose of illustration, itwill be understood that the practice of the invention encompasses all ofthe usual variations, adaptations and/or modifications as come withinthe scope of the following claims and their equivalents.

1. A compound of formula (I)

wherein R¹ is selected from the group consisting of hydrogen, halogen,cyano, nitro, CF₃ and —O—SO₂—CF₃; R² is selected from the groupconsisting of hydrogen, halogen, cyano, nitro, CF₃ and —O—SO₂—CF₃;provided that R¹ and R² are not each hydrogen; a is an integer from 0 to1; L¹ is selected from the group consisting of —C(O)—, —CH(OH)— and—C(O)—NR^(A)—; wherein R^(A) is selected from hydrogen or C₁₋₄alkyl; R³is selected from the group consisting of hydrogen, C₁₋₄alkyl, C₂alkenyl,aryl and heteroaryl; wherein the aryl or heteroaryl is optionallysubstituted with one or more substituents independently selected fromhalogen, hydroxy, C₁₋₄alkyl, C₁₋₄alkoxy, cyano, nitro or CF₃;alternatively, -L¹-R³ is selected from methoxy methyl or2-(Trimethylsilyl)ethoxy methyl; provided that when a is 0, then R³ isother than hydrogen or C₁₋₄alkyl; provided further that when a is 1 andL¹ is —CH(OH)—, then R³ is other than hydrogen; R⁴ is selected from thegroup consisting of hydrogen, aryl, —C(O)-aryl, 6-membered heteroaryland —C(O)-(6 membered heteroaryl); wherein the aryl or heteroaryl group,whether alone or as part of a substituent group is optionallysubstituted with one or more substituents independently selected fromhalogen, hydroxy, C₁₋₄alkyl, C₁₋₄alkoxy, cyano, nitro or CF₃; providedthat when R¹ is hydrogen or halogen, R² is hydrogen, a is 0 and R³ is4-hydroxy-phenyl, then R⁴ is other than 4-chlorophenyl; provided furtherthat when R¹ is halogen, R² is hydrogen, a is 1, L¹ is —C(O)NH— and R³is phenyl, then R⁴ is other than hydrogen; or a pharmaceuticallyacceptable salt thereof.
 2. A compound as in claim 1, wherein R¹ isselected from the group consisting of hydrogen, halogen, cyano, CF₃ and—O—SO₂—CF₃; R² is selected from the group consisting of hydrogen,halogen, cyano, CF₃ and —O—SO₂—CF₃; provided that R¹ and R² are not eachhydrogen; a is an integer from 0 to 1; L¹ is selected from the groupconsisting of —C(O)—, —CH(OH)— and —C(O)—NR^(A)—; wherein R^(A) isselected from hydrogen or C₁₋₄alkyl; R³ is selected from the groupconsisting of hydrogen, C₁₋₄alkyl and aryl; wherein the aryl isoptionally substituted with one or more independently selected fromhalogen, hydroxy, C₁₋₄alkyl, C₁₋₄alkoxy, cyano, nitro or CF₃;alternatively, L¹-R³ is methoxy methyl or 2-(Trimethylsilyl)ethoxymethyl; provided that when a is 0, then R³ is other than hydrogen orC₁₋₄alkyl; provided further that when a is 1 and L¹ is —CH(OH)—, then R³is other than hydrogen; R⁴ is selected from the group consisting ofhydrogen, —CH═CH—, aryl and —C(O)-aryl; wherein the aryl, whether aloneor as part of a substituent group, is optionally substituted with one ormore independently selected from halogen, hydroxy, C₁₋₄alkyl,C₁₋₄alkoxy, cyano, nitro or CF₃; provided that when R¹ is hydrogen orhalogen, R² is hydrogen, a is 0 and R³ is 4-hydroxy-phenyl, then R⁴ isother than 4-chlorophenyl; provided further that when R¹ is halogen, R²is hydrogen, a is 1, L¹ is —C(O)NH— and R³ is phenyl, then R⁴ is otherthan hydrogen; or a pharmaceutically acceptable salt thereof.
 3. Acompound as in claim 2, wherein R¹ is selected from the group consistingof halogen, cyano and —O—SO₂—CF₃; R² is selected from the groupconsisting of hydrogen, cyano and —O—SO₂—CF₃; a is an integer from 0 to1; L¹ is selected from the group consisting of —C(O)—, —CH(OH)— and—C(O)—NR^(A)—; wherein R^(A) is selected from hydrogen, methyl or ethyl;R³ is selected from the group consisting of hydrogen, C₁₋₄alkyl,—CH═CH—, and aryl; wherein the aryl is optionally substituted with oneor more independently selected from halogen; alternatively, L¹-R³ ismethoxy methyl; provided that when a is 0, then R³ is other thanhydrogen or C₁₋₄alkyl; provided further that when a is 1 and L¹ is—CH(OH)—, then R³ is other than hydrogen; R⁴ is selected from the groupconsisting of hydrogen, aryl and —C(O)-aryl; wherein the aryl isoptionally substituted with one to two substituents independentlyselected from hydroxy, halogen, C₁₋₄alkoxy or cyano; provided that whenR¹ is halogen, R² is hydrogen, a is 1, L¹ is —C(O)NH— and R³ is phenyl,then R⁴ is other than hydrogen; or a pharmaceutically acceptable saltthereof.
 4. A compound as in claim 3, wherein R¹ is selected from thegroup consisting of fluoro, cyano and —O—SO₂—CF₃; R² is selected fromthe group consisting of hydrogen, cyano and —O—SO₂—CF₃; a is an integerfrom 0 to 1; L¹ is selected from the group consisting of —C(O)—,—CH(OH)— and —C(O)—NH—; R³ is selected from the group consisting ofhydrogen, methyl, —CH═CH—, 2-chlorophenyl, 3-chlorophenyl,4-chlorophenyl, 2,3-dichlorophenyl, 2,4,-dichlrophenyl,2,4,6-trichlorophenyl, 2-fluorophenyl and 2,4-difluorophenyl;alternatively, L¹-R³ is methoxy methyl provided that when a is 0, thenR³ is other than hydrogen or methyl; provided further that when a is 1and L¹ is —CH(OH)—, then R³ is other than hydrogen; R⁴ is selected fromthe group consisting of hydrogen, 2,4-dihydroxyphenyl,2,4-dimethoxyphenyl, 2-hydroxy-4-cyano-phenyl and4-chlorophenyl-carbonyl-; or a pharmaceutically acceptable salt thereof.5. A compound as in claim 4 selected from the group consisting oftrifluoro-methanesulfonic acid3-(2,4-dimethoxy-phenyl)-4-(2-methoxy-ethyl)-2-oxo-2H-chromen-7-ylester;3-(2,4-dihydroxy-phenyl)-2-oxo-4-vinyl-2H-chromene-7-carbonitrile;trifluoro-methanesulfonic acid4-[2-(2,4-dichloro-phenyl)-2-hydroxy-ethyl]-2-oxo-2H-chromen-7-yl ester;trifluoro-methanesulfonic acid2-oxo-4-[(2,4,6-trichloro-phenylcarbamoyl)-methyl]-2H-chromen-7-ylester; 2-(7-cyano-2-oxo-2H-chromen-4-yl)-N-(2-fluoro-phenyl)-acetamide;N-(3-chloro-phenyl)-2-(7-cyano-2-oxo-2H-chromen-4-yl)-acetamide; or apharmaceutically acceptable salt thereof.
 6. A pharmaceuticalcomposition comprising a pharmaceutically acceptable carrier and acompound of claim
 1. 7. A pharmaceutical composition made by mixing acompound of claim 1 and a pharmaceutically acceptable carrier.